Survival In Castration-resistant Prostate Cancer Research Articles

A Hangover Under 177 Lu-PSMA-617 Therapy : A Red Flag for Brain 68 Ga-PSMA-11 PET/MRI?

Leptomeningeal carcinomatosis in prostate cancer is extremely rare. Because of the low overall penetration of drugs into the brain and the prolonged survival of castration-resistant prostate cancer (CRPC) patients, a special attention should be paid to the appearance of neurological symptoms in long-term CRPC survivors. A patient suffering from a CRPC with bone metastases underwent 4 cycles of 177 Lu-PSMA (prostate-specific membrane antigen)-617. Starting from the third cycle, he reported an increasing feeling of a permanent hangover. A 68 Ga-PSMA-11 brain PET/MRI was carried out after the fourth cycle. It revealed intraparenchymatous brain metastases with intense uptake and evidences of leptomeningeal carcinomatosis.

Sambucus nigra agglutinin as a supporter of docetaxel treatment in metastatic prostate cancer

Androgen deprivation therapy (ADT) has been the first treatment for advanced prostate cancer. Although 90% of patients initially respond to ADT, the disease inevitably progresses to castration-resistant prostate cancer (CRPC). Docetaxel was reported to provide significant benefit over other chemotherapeutics in prolonging survival in CRPC. Recently, other chemotherapeutics have been used in cases where docetaxel is insufficient or the patient develops resistance, but yet their efficacy is limited. For this reason, it is necessary to develop docetaxel-based therapy, reduce toxicity, increase treatment efficiency. It has been shown that the non-toxic plant lectin Sambucus nigra agglutinin (SNA) drives ovarian cancer cells to the apoptotic pathway. Increased sialic acid levels in prostate cancer have suggested that SNA lectin, which binds to glycan sialic acid residues, may also have an activating effect on the apoptotic pathway for prostate cancer. In order to evaluate this, docetaxel and SNA were applied to DU-145 cells alone and in combination. Arterwards XTT cytotoxicity test, RNA isolation, cDNA synthesis, gene expression analysis by real time PCR method were performed. In our study, SNA alone did not show any effect on prostate cancer cells whereas it increased the efficacy of docetaxel. Furthermore, our study showed for the first time that SNA + docetaxel has a synergistic effect on the increase in Bim and decrease in Drp1expressions. Based on the data obtained from the current study, it is thought that the use of the SNA + docetaxel combination in the treatment of metastatic prostate cancer will increase the treatment efficacy.

Discovery of a highly potent and orally available importin-β1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer

Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.

A first-in-class HBO1 inhibitor WM-3835 inhibits castration-resistant prostate cancer cell growth in vitro and in vivo

The prognosis and overall survival of castration-resistant prostate cancer (CRPC) patients are poor. The search for novel and efficient anti-CRPC agents is therefore extremely important. WM-3835 is a cell-permeable, potent and first-in-class HBO1 (KAT7 or MYST2) inhibitor. Here in primary human prostate cancer cells-derived from CRPC patients, WM-3835 potently inhibited cell viability, proliferation, cell cycle progression and in vitro cell migration. The HBO1 inhibitor provoked apoptosis in the prostate cancer cells. It failed to induce significant cytotoxicity and apoptosis in primary human prostate epithelial cells. shRNA-induced silencing of HBO1 resulted in robust anti-prostate cancer cell activity as well, and adding WM-3835 failed to induce further cytotoxicity in the primary prostate cancer cells. Conversely, ectopic overexpression of HBO1 further augmented primary prostate cancer cell proliferation and migration. WM-3835 inhibited H3-H4 acetylation and downregulated several pro-cancerous genes (CCR2, MYLK, VEGFR2, and OCIAD2) in primary CRPC cells. Importantly, HBO1 mRNA and protein levels are significantly elevated in CRPC tissues and cells. In vivo, daily intraperitoneal injection of WM-3835 potently inhibited pPC-1 xenograft growth in nude mice, and no apparent toxicities detected. Moreover, intratumoral injection of HBO1 shRNA adeno-associated virus (AAV) suppressed the growth of primary prostate cancer xenografts in nude mice. H3-H4 histone acetylation and HBO1-dependent genes (CCR2, MYLK, VEGFR2, and OCIAD2) were remarkably decreased in WM-3835-treated or HBO1-silenced xenograft tissues. Together, targeting HBO1 by WM-3835 robustly inhibits CRPC cell growth.

Effectiveness of Current First-Line Treatments and Evaluation of Prognostic Factors Related to Survival in Castration-Resistant Prostate Cancer with Isolated Bone Metastasis

Effectiveness of Current First-Line Treatments and Evaluation of Prognostic Factors Related to Survival in Castration-Resistant Prostate Cancer with Isolated Bone Metastasis

Outcomes and Factors Associated with Completion of Radium-223 Therapy.

Radium-223 has been demonstrated in clinical trials to improve survival in castration-resistant prostate cancer (CRPC) patients with bone metastases. However, its performance in routine use remains to be fully characterized. This study aims to describe patient outcomes in the real world as well as identify factors associated with completion of the 6-dose regimen and alkaline phosphatase (ALP) response. Thirty-six patients who received at least one dose of radium-223 at the Jewish General Hospital in Montréal, Canada, were analysed in a retrospective manner. Using logistic regression, the primary analysis aimed to identify factors associated with treatment completion, and the secondary analysis aimed to identify factors associated with ALP response. Twenty-one out of 36 patients received all 6 doses of radium-223. Fifteen patients had an ALP response, defined as a 30% decrease in ALP from baseline values. On primary analysis, baseline ALP > 120 U/L and prostate-specific antigen (PSA) > 50μg/L were significantly associated with lower therapy completion rates (OR = 0.10, p = 0.004; OR = 0.18, p = 0.022 respectively). On adjustment for confounders, only ALP remained significant (OR = 0.14, p = 0.021). Clinical disease progression was the most common reason for treatment non-completion, and it was also associated with elevated baseline ALP (OR = 6.00, p = 0.044). On secondary analysis, previous chemotherapy for CRPC was a negative predictor of ALP response (OR = 0.15, p = 0.034). Elevated baseline ALP and PSA were associated with a lower rate of radium-223 regimen completion; receiving chemotherapy for CRPC prior to radium-223 was associated with a lower rate of ALP response. The online version contains supplementary material available at 10.1007/s13139-022-00760-8.

Enzalutamide Versus Abiraterone plus Prednisolone Before Chemotherapy for Castration-resistant Prostate Cancer: A Multicenter Randomized Controlled Trial

BackgroundEnzalutamide (ENZ) and abiraterone plus prednisolone (ABI) improve survival in castration-resistant prostate cancer (CRPC). However, which agent is better for patients with CRPC remains unclear. ObjectiveTo evaluate whether ENZ or ABI is better as first-line treatment for CRPC. Design, setting, and participantsAn investigator-initiated, multicenter, randomized controlled trial was conducted in Japan. The study enrolled 203 patients with CRPC before chemotherapy between February 20, 2015, and July 31, 2019. Patients were randomly assigned 1:1 to the ENZ or ABI arm. Outcome measurements and statistical analysisThe primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included the PSA response rate (≥50% decline from baseline), overall survival, and safety. A log-rank test was used for comparison of survival analyses between arms. Results and limitationsAfter randomization, 92 patients in each arm were treated and analyzed. Time to PSA progression did not significantly differ between the arms (median 21.2 mo for ENZ and 11.9 mo for ABI; hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.51–1.27; p = 0.1732). There was a significant difference in the PSA response rate between the arms (72% for ENZ and 57% for ABI; p = 0.0425). There was no significant difference in overall survival (median 32.9 mo for ENZA and 35.5 mo for ABI; HR 1.17, 95% CI 0.72–1.88; p = 0.5290). Grade ≥3 adverse events were observed in 11% of patients in the ENZA arm and 21% in the ABI arm (p = 0.1044). ConclusionsENZ did not show any survival benefit in comparison to ABI, but showed a better PSA response rate with a low rate of severe adverse events in CRPC. Patient summaryResults from our study suggest that use of enzalutamide before abiraterone may have potential clinical benefits for patients with castration-resistant prostate cancer.

Enzalutamide versus abiraterone plus prednisolone before chemotherapy for Japanese castration-resistant prostate cancer patients: An investigator-initiated, multicenter, randomized controlled trial.

122 Background: Enzalutamide and abiraterone plus prednisolone demonstrated improvement of survival for castration-resistant prostate cancer (CRPC). However, it remains quite unclear which agent is better in terms of efficacy and safety for Asian patients. Methods: An investigator-initiated, multicenter, randomized controlled trial was conducted in Japan. CRPC patients before chemotherapy were randomly assigned to the enzalutamide or the abiraterone plus prednisolone arm (1:1). The primary endpoint is time to prostate-specific antigen (PSA) progression and secondary endpoints include PSA response rate (≥50% decline from baseline), overall survival, radiographic progression-free survival, and safety assessment. Results: Between February 20, 2015 and July 30, 2019, 203 patients were enrolled. After randomization, 92 in the enzalutamide and 92 in the abiraterone plus prednisolone arm were treated and analyzed. Time to PSA progression was not significantly different between arms (median 21.2 and 11.9 months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 0.81, 95% CI 0.51-1.27, p = 0.1732). There was a significant difference in PSA response rate between arms (72% and 57% in the enzalutamide and the abiraterone plus prednisolone arm, respectively, p = 0.0425). There were no significant differences in overall and radiographic progression-free survival between arms (median 32.9 and 35.5months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 1.17, 95% CI 0.72-1.88, p = 0.5290 and median 17.6 and 14.0 months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 0.92, 95% CI 0.63-1.34, p = 0.6532). Grade ≥3 of adverse events were observed in 11% and 21% in the enzalutamide and the abiraterone plus prednisolone arm, respectively ( p = 0.1044). Conclusions: Enzalutamide did not show any survival benefits compared with abiraterone plus prednisolone but showed better PSA response rate with no significant differences of severe adverse event rate for Japanese CRPC patients. Our data suggest that antecedent use of enzalutamide to abiraterone plus prednisolone have potentially clinical benefits in Asian CRPC populations. Clinical trial information: UMIN000015529.

A novel small-molecule activator of unfolded protein response suppresses castration-resistant prostate cancer growth

Androgen receptor-targeted therapy improves survival in castration-resistant prostate cancer (CRPC). However, almost all patients with CRPC eventually develop secondary resistance to these drugs. Therefore, alternative therapeutic approaches for incurable metastatic CRPC are urgently needed. Unfolded protein response (UPR) is regarded as a cytoprotective mechanism that removes misfolded proteins in rapidly proliferating tumor cells. However, acute activation of the UPR directly leads to tumor cell death. This study has shown that WJ-644A, a novel small molecule activator of UPR, potently inhibited the proliferation of prostate cancer cells and caused tumor regression with a good safety profile in multiple animal models. Mechanistically, we have identified that WJ-644A induced cell methuosis and autophagy upon UPR activation. Our study not only identifies the UPR as an actionable target for CRPC treatment, but also establishes WJ-644A as a novel UPR activator that has potential therapeutic value for CRPC.

EFFECT OF NEW ANDROGEN RECEPTOR AXIS-TARGETED AGENTS ON SURVIVAL OF CASTRATION-RESISTANT PROSTATE CANCER

(Background)The real world's effect of new androgen receptor axis-targeted agents (ARATs) on survival of castration-resistant prostate cancer (CRPC) remains unclear in Japan. (Aims)The primary aim was to determine the clinical benefit of ARATs on survival of CRPC patients. The secondary aim was to evaluate predictive factors affecting the survival of CRPC patients. (Patients and results)Among 236 patients treated with androgen deprivation therapy (ADT), 68 patients developed CRPC; two groups of 34 patients were treated with ARATs (A cases) or conventional ADT (V cases). In a median follow-up of 61.5 months, 20 A and 22 V cases died of cancer. Median survival time (MST) from diagnosis was 99 and 66 months for A and V cases, respectively, and MST from CRPC to death were 50.5 and 44.5 months, respectively. There were no significant differences between both cases. The hazard ratio for death from diagnosis or CRPC progression of the A cases to V cases was 0.711; 95% confidence interval (CI), 0.371 to 1.362; P = 0.3037, or 0.805; 95% CI, 0.434 to 1.491; P=0.4899, respectively. Multivariable analysis revealed that a unique and significant independent prognostic factor from diagnosis was time to CRPC. (Conclusions)In this small retrospective study, we could not determine the clinical benefit of new ARATs compared with conventional ADT on survival of CRPC patients, and a unique and significant independent prognostic factor from diagnosis was time to CRPC. We need to validate these results in a future multi-institutional study.

Risk Scoring System for Ra-223 Discontinuation and Its Effect on Prognosis: A Retrospective Study.

Radium-223 therapy prolongs overall survival in castration-resistant prostate cancer (CRPC) patients with bone metastasis. Patients who are unable to complete six courses of radium-223 therapy reportedly have a poor prognosis. This study aimed to develop a risk score using the discontinuation factors of the above therapy modality. Seventy patients who received radium-223 therapy for metastatic CRPC at two Japanese Institutions were evaluated. Univariate and multivariate analyses were performed to identify the discontinuation factors and determine the risk scores. The median survival time was 24.3 and 9.5 months in patients who did and did not complete the therapy, respectively. Multivariate analysis revealed haemoglobin and prostate-specific antigen as key factors. A risk score was developed using these factors, and patients were stratified into three groups. The discontinuation rate and survival after radium-223 therapy were significantly different. Our risk score may help evaluate the suitability of radium-223 in CRPC patients.

Serum and hematologic responses after three cycles of cabazitaxel therapy as predictors of survival in castration-resistant prostate cancer.

In this study, we investigated the association between the early response of serum and hematological variables and the outcome of cabazitaxel therapy. The medical records of 59 consecutive patients who had previously received docetaxel chemotherapy for the treatment of metastatic castration-resistant prostate cancer (CRPC) and who received cabazitaxel at our hospital between January 2011 and March 2020 were retrospectively reviewed and statistically analyzed. The median follow-up period after cabazitaxel initiation was 15.2months. The 30% prostate-specific antigen (PSA) response rate, median PSA progression-free survival period, and overall survival (OS) period were 45.8%, 4.3months, and 22.6months, respectively. Within 1 to 2 cycles of cabazitaxel, we were unable to identify hematological or serum kinetics that had a relationship with OS. Analysis of the variables after 3 cycles of cabazitaxel, however, revealed two factors, PSA decline > 30% (p = 0.016) and neutrophil-lymphocyte ratio (NLR) decline > 30% (p = 0.044), as the predictors of favorable outcome for OS. We established a prognostic model for predicting the OS period composed of these two factors, which exhibited distinctly separated OS curves (p = 0.004). The C-index of a model incorporating these two factors was 0.703. This is the first study to demonstrate that PSA and NLR decline 3 cycles after the initiation of cabazitaxel were associated with favorable outcome in patients with CRPC. Also, 3 cycles of cabazitaxel might be necessary to assess the efficacy of cabazitaxel therapy.

Integration of circulating tumor cell and neutrophil-lymphocyte ratio to identify high-risk metastatic castration-resistant prostate cancer patients

BackgroundThe neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and circulating tumor cells (CTCs) have been associated with survival in castration-resistant prostate cancer (CRPC). However, no study has examined the prognostic value of NLR and PLR in the context of CTCs.MethodsBaseline CTCs from mCRPC patients were enumerated using the CellSearch System. Baseline NLR and PLR values were calculated using the data from routine complete blood counts. The associations of CTC, NLR, and PLR values, individually and jointly, with progression-free survival (PFS) and overall survival (OS), were evaluated using Kaplan-Meier analysis, as well as univariate and multivariate Cox models.ResultsCTCs were detected in 37 (58.7%) of 63 mCRPC patients, and among them, 16 (25.4%) had ≥5 CTCs. The presence of CTCs was significantly associated with a 4.02-fold increased risk for progression and a 3.72-fold increased risk of death during a median follow-up of 17.6 months. OS was shorter among patients with high levels of NLR or PLR than those with low levels (log-rank P = 0.023 and 0.077). Neither NLR nor PLR was individually associated with PFS. Among the 37 patients with detectable CTCs, those with a high NLR had significantly shorter OS (log-rank P = 0.024); however, among the 26 patients without CTCs, the OS difference between high- and low-NLR groups was not statistically significant. Compared to the patients with CTCs and low NLR, those with CTCs and high levels of NLR had a 3.79-fold risk of death (P = 0.036). This association remained significant after adjusting for covariates (P = 0.031). Combination analyses of CTC and PLR did not yield significant results.ConclusionAmong patients with detectable CTCs, the use of NLR could further classify patients into different risk groups, suggesting a complementary role for NLR in CTC-based prognostic stratification in mCRPC.

Genome-wide Expression Analysis Identifies the Association between SEC14L2 and Castration-resistant Prostate Cancer Survival.

Background: Mechanism of castration-resistant prostate cancer (CRPC) is still unclear. Our objective is to investigate the association between genes expression and CRPC through the genome-wide approach and functional researches.Methods: Differentially expressed genes (DEGs) between PCa and CRPC tissues were identified using expression profile obtained from Gene Expression Omnibus database (GEO). Survival analysis was performed using online database Gene Expression Profiling Interactive Analysis (GEPIA). Oncomine database was further used to explore the relationship between DEGs expression levels with clinical parameters. After in silico study, SEC14L2-knockdown CRPC cells and normal prostatic epithelial cells were used for in vitro study to verify its biological functions.Results: A total of 3 consistently changed DEGs (SEC14L2, DMD, SEL1L) were identified correlating with CRPC after cross validation in three independent datasets. Low expression of SEC14L2 was associated with poorer disease-free survival and higher Gleason score than normal/high expression of SEC14L2. SEC14L2 knockdown promoted cell proliferation, migration, invasion as well as cell cycle progression in CRPC cells (all P<0.05) while no significant effects were observed in normal prostatic epithelial cells.Conclusions: Low expression of SEC14L2 was significantly associated with CRPC, and correlated with PCa aggressiveness and poorer prognosis. SEC14L2 might be a potential biomarker or drug target for CRPC.

Prognostic value of ECOG performance status and Gleason score in the survival of castration-resistant prostate cancer: a systematic review.

Eastern Cooperative Oncology Group (ECOG) performance status and Gleason score are commonly investigated factors for overall survival (OS) in men with castration-resistant prostate cancer (CRPC). However, there is a lack of consistency regarding their prognostic or predictive value for OS. Therefore, we performed this meta-analysis to assess the associations of ECOG performance status and Gleason score with OS in CRPC patients and compare the two markers in patients under different treatment regimens or with different chemotherapy histories. A systematic literature review of monotherapy studies in CRPC patients was conducted in the PubMed database until May 2019. The data from 8247 patients in 34 studies, including clinical trials and real-world data, were included in our meta-analysis. Of these, twenty studies reported multivariate results and were included in our main analysis. CRPC patients with higher ECOG performance statuses (≥ 2) had a significantly increased mortality risk than those with lower ECOG performance statuses (<2), hazard ratio (HR): 2.10, 95% confidence interval (CI): 1.68–2.62, and P < 0.001. The synthesized HR of OS stratified by Gleason score was 1.01, with a 95% CI of 0.62–1.67 (Gleason score ≥ 8 vs <8). Subgroup analysis showed that there was no significant difference in pooled HRs for patients administered taxane chemotherapy (docetaxel and cabazitaxel) and androgen-targeting therapy (abiraterone acetate and enzalutamide) or for patients with different chemotherapy histories. ECOG performance status was identified as a significant prognostic factor in CRPC patients, while Gleason score showed a weak prognostic value for OS based on the available data in our meta-analysis.

Abstract 4761: Lipidomic analysis of circulating lipids across the natural history of prostate cancer identifies aberrant ceramide metabolism

Abstract Background: Obesity is a well established risk factor not only for increased prostate cancer incidence, but for poorer survival from prostate cancer. However, there is limited knowledge on the role of the circulating lipidome in prostate cancer. In order to target lipid metabolism optimally, it is critical to understand the spectrum of changes in circulating lipid profiles and the association with clinical outcome across the natural history of prostate cancer. Aim: To assess the relationship between the plasma lipidome and clinical outcome in localized and metastatic prostate cancer. Methods: Liquid chromatography-tandem mass spectrometry was used to quantitate over 500 lipid species in plasma samples from 3 cohorts (1) 389 men with localized prostate cancer, (2) 44 men with metastatic hormone-sensitive prostate cancer (mHSPC), and (3) 137 men with metastatic castration-resistant prostate cancer (CRPC). Associations between circulating lipids with metastatic relapse, androgen-deprivation therapy (ADT) failure or overall survival for each relevant disease stage were examined by latent class analysis and cox regression. Results: Circulating lipid profiles displaying elevated levels of ceramides were associated with metastatic relapse in localized prostate cancer (HR 5.8, 95% CI 3.0-11, P 1 × 10−6), early ADT failure in mHSPC (HR 2.4, 95% CI 1.1-5.3, P 0.03), and shorter overall survival in CRPC (HR 2.5, 95% CI 1.7-3.7, P 2 × 10−6). ADT failure in mHSPC and shorter overall survival in CRPC were also associated with elevated levels of other sphingolipids (sphingomyelins, hexosylceramides). The prognostic significance of the high risk lipid profiles in localized prostate cancer was independent of clinicopathological characteristics (lipid profile HR 4.7, 95%CI 2.4-9.3, P 7 × 10−6) when modeled with Gleason score (P&amp;lt;0.0001) and pathological stage (P&amp;lt;0.0001). Furthermore, the circulating lipid profiles were independent of metabolic factors (localized prostate cancer lipid profile HR 8.2, 95% CI 2.6-25, P 0.0003 when modeled with diabetes, statin, hypertension, body mass index [BMI]; CRPC lipid profile HR 2.6, 95% CI 1.7-3.8, P x10−6 when modeled with BMI). Conclusion: Elevated circulating ceramides are associated with poorer clinical outcomes across the natural history of prostate cancer (from localized to metastatic hormone-sensitive to metastatic castration resistant prostate cancer). This demonstrates that aberrant lipid metabolism in the patients occurs early in prostate cancer and could be therapeutically targeted in prospective clinical trials to improve prostate cancer outcomes. Citation Format: Lisa Glen Horvath, Hui-Ming Lin, Blossom Mak, Kate Mahon, Nicole Yeung, Maria Docanto, Peter Sutherland, andrew Shepherd, Winston Tan, Arun Azad, Manish Kohli, Peter Meikle, Lisa Butler. Lipidomic analysis of circulating lipids across the natural history of prostate cancer identifies aberrant ceramide metabolism [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4761.

Nursing Implications of Recent Changes in Management Practices for Metastatic Prostate Cancer.

Prostate cancer is one of the most common male cancers in the world and accounts for substantial morbidity, mortality, loss of disability-adjusted life-years, and financial burden to patients and to the community. Metastatic prostate cancer has been managed for over 70 years with androgen deprivation therapy, but further life-prolonging therapies were not available until 2004. Since then, drugs such as docetaxel, abiraterone, enzalutamide, cabazitaxel, radium-223 dichloride, and (not available in Australia) sipuleucel-T have all demonstrated efficacy in prolongation of survival in castrate-resistant prostate cancer, and improvement in cancer-related morbidity. Peer-reviewed scientific publications, Australian Government agency reports, and expert opinion. More recently, several of these agents have been given earlier in the treatment course to the hormone-sensitive metastatic setting, with even greater benefits in survival. These treatments have come at a cost: a literal financial cost to the community, and often to the patients and their families; and financial costs to the community to supply the drugs to those who need them. They also carry non-financial costs, including side effects of treatment, exacerbation of other co-morbidities, metabolic and bone health challenges, and psychological and social stresses, including those associated with longer survival with metastatic cancer. The role of the nurse in management of these issues has never been more important. Nurses are often uniquely placed to educate men with prostate cancer and their families, screen for and identify adverse effects of treatment, and provide education and support not otherwise available. Nurses are central to the streamline of care coordination within the multidisciplinary team and the holistic care journey for men and their partners through the health care system. This review discusses several of these aspects to inform practice.

Determining the prognostic significance of IKKα in prostate cancer.

As the survival of castration-resistant prostate cancer (CRPC) remains poor, and the nuclear factor-κB (NF-κB) pathways playkey roles in prostate cancer (PC) progression, several studies have focused on inhibiting the NF-κB pathway through generating inhibitory κB kinase subunitα (IKKα) small molecule inhibitors. However, the identification of prognostic markers able to discriminate which patients could benefit from IKKα inhibitors is urgently required. The present study investigated the prognostic value of IKKα, IKKα phosphorylated at serine 180 (p-IKKα S180) and threonine 23 (p-IKKα T23), and their relationship with the androgen receptor (AR) and Ki67 proliferation index to predict patient outcome. A cohort of 115 patients with hormone-naïve PC (HNPC) and CRPC specimens available were used to assess tumor cell expression of proteins within both the cytoplasm and the nucleus by immunohistochemistry. The expression levels were dichotomized (low vs high) to determine the associations between IKKα, AR, Ki67, and patients'Isurvival. In addition, an analysis was performed to assess potential IKKα associations with clinicopathological and inflammatory features, and potential IKKα correlations with other cancer pathways essential for CRPC growth. High levels of cytoplasmic IKKα were associated with a higher cancer-specific survival in HNPC patients with low AR expression (hazards ratio [HR], 0.33; 95% confidence interval [CI] log-rank, 0.11-0.98; P = .04). Furthermore, nuclear IKKα (HR, 2.60; 95% CI, 1.27-5.33; P = .01) and cytoplasmic p-IKKα S180 (HR, 2.10; 95% CI, 1.17-3.76; P = .01) were associated with a lower time to death from recurrence in patients with CRPC. In addition, high IKKα expression was associated with high levels of T-cells (CD3+ P = .01 and CD8+ P = .03) in HNPC; however, under castration conditions, high IKKα expression was associated with high levels of CD68+ macrophages (P = .04), higher Gleason score (P = .01) and more prostate-specific antigen concentration (P = .03). Finally, we identified crosstalk between IKKα and members of the canonical NF-κB pathway in the nucleus of HNPC. Otherwise, IKKα phosphorylated by noncanonical NF-κB and Akt pathways correlated with members of the canonical NF-κB pathway in CRPC. The present study reports that patients with CRPC expressing high levels of nuclear IKKα or cytoplasmic p-IKKα S180, which associated with a lower time to death from recurrence, may benefit from IKKα inhibitors.

Bipolar androgen therapy in prostate cancer: Current evidences and future perspectives.

Testosterone suppression by androgen deprivation therapy is the cornerstone of prostate cancer treatment. New-generation hormone therapies improved overall survival in castration-resistant prostate cancer. More recent trials showed a further increase in overall survival when enzalutamide or abiraterone are associated with androgen deprivation therapy in hormone-sensitive disease. However, a higher clonal pressure may lead to the upregulation of alternative pathways for cancer progression and to dedifferentiated diseases that would probably respond poorly to subsequent treatments. In this contest, new strategies that could be able to delay or even revert resistance are needed. The bipolar androgen therapy is an under-investigation treatment that consists in periodical oscillation between castration levels and supraphysiological levels of testosterone in order to prevent the adaptation of prostate cancer cells to a low-androgen environment. This review aims to underline the biological rationale of bipolar androgen therapy and gather evidences from the most recent clinical trials.

MP37-06 MUSCLE CHARACTERISTICS OBTAINED FROM COMPUTED TOMOGRAPHY MAY BE PROGNOSTICATORS IN CASTRATION-RESISTANT PROSTATE CANCER PATIENTS: A SINGLE-CENTER ANALYSIS OF 453 PATIENTS

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III (MP37)1 Apr 2020MP37-06 MUSCLE CHARACTERISTICS OBTAINED FROM COMPUTED TOMOGRAPHY MAY BE PROGNOSTICATORS IN CASTRATION-RESISTANT PROSTATE CANCER PATIENTS: A SINGLE-CENTER ANALYSIS OF 453 PATIENTS Jongsoo Lee*, Ji Eun Heo, Won Sik Jang, Won Sik Ham, Koon Ho Rha, and Young Deuk Choi Jongsoo Lee*Jongsoo Lee* More articles by this author , Ji Eun HeoJi Eun Heo More articles by this author , Won Sik JangWon Sik Jang More articles by this author , Won Sik HamWon Sik Ham More articles by this author , Koon Ho RhaKoon Ho Rha More articles by this author , and Young Deuk ChoiYoung Deuk Choi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000886.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To analyze the effect of muscle mass and quality on the prognosis of patients with castration-resistant prostate cancer. METHODS: Skeletal muscle area and attenuation were measured in the L3 vertebra using computed tomography at the time of CRPC diagnosis to obtain skeletal muscle index (SMI, cm2/m2) and skeletal muscle attenuation (SMA, Hounsfield unit [HU]), which were evaluated as prognosticators of CRPC. In addition, to understand the value of SMI and SMA in the elderly, subgroup analysis was conducted in patients aged <70 and >70 years. RESULTS: In total, 411 patients were included. The median values of skeletal muscle index and skeletal muscle attenuation were 45.2 cm2/m2 and 32.4 Hounsfield unit, respectively. The median survival rate for patients with low and high skeletal muscle index and skeletal muscle attenuation was 19 and 24 and 15 and 26 months, respectively (p=0.015 and p<0.001, respectively). In multivariate analysis, prostate-specific antigen, hemoglobin, alkaline phosphatase, bone metastasis, lymph node metastasis, visceral metastasis, and skeletal muscle attenuation were statistically significant. In subgroup analysis of patients aged <70 and >70 years, skeletal muscle attenuation was a significant prognosticator in both groups, whereas skeletal muscle index was a significant prognosticator only in patients aged >70 years. CONCLUSIONS: Skeletal muscle index and skeletal muscle attenuation can be predictors of survival in castration-resistant prostate cancer. In the era of development of imaging technique, they may substitute body mass index or body surface area as health indexes or dose determinants of medications. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e562-e562 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jongsoo Lee* More articles by this author Ji Eun Heo More articles by this author Won Sik Jang More articles by this author Won Sik Ham More articles by this author Koon Ho Rha More articles by this author Young Deuk Choi More articles by this author Expand All Advertisement PDF downloadLoading ...